1. Intellectual Disability (ID)
Joel Charrow, MD

2. Intelligence is what the IQ tests measure.

3. The Wechsler Intelligence Scale for Children
Full Scale IQ (“General Intelligence”)
Verbal IQ
Information (facts)
Vocabulary (definitions)
Arithmetic (word problems)
Comprehension (social understanding)
Similarities
Performance IQ (Visual-spatial)
Picture completion
Block design (copy block arrangements from models and pictures)
Object assembly (puzzles)
Picture arrangement (order cartoons to tell a story)
Coding (use symbols to code and decode, with a key)

4. “Mental Age”
IQ = x 100
Chronologic Age

6. 34.1%
34.1%
13.6%
13.6%
2.1%
2.1%

7. } 5 Approximate Percentage of Intellectually Disabled Population
Severity of Intellectual Disability IQ
Mild (“educable”) 75
Moderate (“trainable”) 20
Severe }
Profound
< 20

8. } } Mild 50-70 Moderate 35-49 Severe 20-34 Profound <20 Severe

9. } } } } } Frequency Size exaggerated Profound <20 Severe 20-34
Moderate
35-49
Mild
50-70

10. Why should we care what causes ID?
There may be treatment (1 -2%)
It’s important to know the course and prognosis
Genetic counseling and family planning!

11. Everyone has a family.

12. Recurrence Risks for Intellectual Disability
When the couple has not had any children
When the couple has had one intellectually disabled child
Risk
Risk
Both parents normal
<1%
Both parents normal %
Both parents normal, intellectually disabled aunt or uncle
Both parents normal, intellectually disabled aunt or uncle
2.5%
13%
One parent intellectually disabled and one parent normal, with one intellectually disabled aunt or uncle
24%
One parent intellectually disabled
20%

13. How common is intellectual disability?
3% of the population is intellectually disabled (~7,000,000 people)
< 0.1% has cystic fibrosis
< 0.01% has PKU
< 0.2% of African Americans have sickle cell disease

14. Origin of Severe Intellectual Disability
Prenatal Origin
Perinatal Origin
Postnatal Origin
Unknown

15. Origin of Severe Intellectual Disability
Single
Gene
Chromosomal
Malformational

16. Karyotype Resolution Standard karyotype (550 – 850 bands)
has relatively low resolution: 3 – 8 MB

17. Array Based Comparative Genomic Hybridization (aCGH)
DNA fragments from known chromosomal locations are bound to a glass slide to form an array.
The DNA in each circle (clone), contains DNA from a specific, known chromosomal location, and is physically bound to the slide.
The DNA clones are selected to cover the entire genome at approximately even intervals.
Chromosome regions of particular interest (e.g., known genes or microdeletion regions) are represented by clones that are closer together on the chromosome.
Microarray
with Genomic
Clones

18. Array Based Comparative Genomic Hybridization (aCGH)
DNA from the patient is fragmented and labeled with a fluorescent tag (e.g., green).
“Control” DNA fragments from a different person is labeled with a fluorescent tag with a different color (e.g., red).
The DNA fragments from the patient and the control are hybridized to the DNA in the array.

19. Array Based Comparative Genomic Hybridization
(aCGH)
Patient DNA
Microarray
with Genomic
Clones
Normal: ratio 0.8 – 1.2
Control DNA

20. Array Based Comparative Genomic Hybridization
(aCGH)
Patient DNA
Microarray
with Genomic
Clones
Loss: ratio <0.8
Normal: ratio
Control DNA

21. Array Based Comparative Genomic Hybridization
(aCGH)
Patient DNA
Microarray
with Genomic
Clones
Loss: ratio <0.8
Normal: ratio
Gain: ratio >1.2
Control DNA

22. Array Based Comparative Genomic Hybridization (aCGH)

23. Array Based Comparative Genomic Hybridization (aCGH)

24. Abnormal Microarray

25. Karyotype vs. Array CGH Density Resolution Karyotype 550 – 850 bands
3 – 8 MB
44K Array
42,494 probes
24 – 43 KB spacing
1M Array
963,029 probes
1.8 – 2.1 KB spacing

26. Origin of Severe Intellectual Disability
Single
Gene
Chromosomal
Malformational

28. The FMR1 Gene CpG island Trinucleotide repeat5' 3'
... CGG CGG CGG CGG CGG CGG ...

29. Expansion of Trinucleotide Repeat
# of Repeats
Phenotype
Normal 28
Normal
Premutation
Normal
Full Mutation
> 200
Intellectually Disabled*
*Penetrance of ID in females is ~53%

30. Risk of Intellectual Disability in Child
# of Repeats in Mother
Frequency of Full Mutation
Son
Daughter*
16% 8% 4%
70%
35%
18%
> 81
100%
50%
26%
*Penetrance of ID in daughters is ~53%

31. The Sherman Paradox Premutation 8% Transmitting male 4% 0% 50% 28%
Full mutation
Normal repeat length
16%
37%
% refers to risk of ID

32. Expansion of Trinucleotide Repeats in FMR-1
Premutations:
Meiotically unstable in oogenesis - tend to expand
Mitotically stable (post-fertilization)
Full mutations:
Mitotically unstable (post-fertilization) - leads to mosaicism for size of expanded repeat

33. Single Gene
Noonan Syndrome
Autosomal dominant

34. Incontinentia Pigmenti Single Gene
(X-linked dominant, lethal in males)
Single Gene

35. Brachman - De Lange Syndrome
(Usually sporadic; Nipped-B-Like gene)

36. Origin of Severe Intellectual Disability
Single
Gene
Chromosomal
Malformational

37. Causes of Severe Intellectual Disability
(Summary of three studies)
Percent
Multiple congenital anomalies
Isolated CNS malformations
Neural tube defects 3
Hydrocephalus 2 - 5
Microcephaly 5
Moser et al., in Emery and Rimoin, 1990

39. Meningomyelocele / Spina Bifida
From: KL Moore, TVN Persaud, K Shiota: Color atlas of clinical embryology. W.B. Saunders Company, Philadelphia, 1994.

40. Anencephaly/Encephalocele

41. Congenital Malformations
Percent of Cases
Unknown 60
Multifactorial 20
Single Genes 7
Teratogens
Chromosome abnormalities 6

42. Causes of Severe Intellectual Disability
(Summary of three studies)
Perinatal (and unidentified
prenatal) causes
Infectious diseases
Postnatal brain injury (non-infectious)
Unclassified
Percent
Moser et al., in Emery and Rimoin, 1990

43. Deterioration IQ
Degeneration
Time

44. I-cell disease
(Mucolipidosis II)

45. History & Physical IQ > 50 Familial ID? IQ < 50 Prenatal Onset
- chromosomal
- MCA
- CNS malformation
- teratogens
Postnatal Onset
- infection
- metabolic
- trauma
Perinatal Onset
- infection
- asphyxia

46. Frequency of Minor and Major Anomalies
Only 1
Only 2
3 or More
1 or More
Patient Group
Minor
Major
Minor
Major
Minor
Major
Minor
Major
Intellectually Disabled 24 18 18 10 32 2 74 30
“Normal” 20 7 2 22 7
Smith & Bostian (1964) J Pediatr 65: